ABSTRACT The traditional ?standard of care? for cancer over the past several decades has consisted of surgery, radiation therapy, chemotherapy, and stem cell transplantation in some cancers such as acute myeloid leukemia. In the last decade, immune therapy using monoclonal antibodies such as rituximab and traztuzumab have now been incorporated into the standard of care for lymphoma and breast cancer, respectively. Compelling data now shows that that innate immune cells, such as natural killer (NK) cells are an important component mediating the clinical effectiveness of antibody therapy. Our proposal aims to strengthen cellular innate immunity to enhance cancer therapy. Part of the challenge relates to 1) limited recognition of tumor cells by innate immune effector cells; 2) dampening of innate immune effector cell function in the tumor microenvironment; and 3) penetration of the tumor mass by innate immune effector cells. Our vision is to add activated, tumor antigen specific innate immune effector cell therapy to the existing armamentarium against both liquid and solid tumors. Strategically, this will be accomplished over the next 7 years through: 1) a more complete understanding human NK cell development, including the expression of activating and inhibitory receptors; 2) optimizing the development of human NK cells expressing chimeric antigen receptors, and 3) full development of our bi-specific NKG2D antibody that will bring human NK cells and other innate immune effector cells into the tumor bed. Our documented consistent success with basic research on NK cell development and effector function over decades, along with our successful translation of a multitude of our discoveries to the clinic in over 1,000 cancer patients both serve as a foundation for us to successfully proceed along this pathway. In the next seven years, we believe we will lead the field in: 1) enhancing NK cell tumor specificity; 2) enhancing NK cell cytolytic effector function; and 3) enhancing migration of NK and other innate immune cells into the tumor bed. The potential outcome over the next 7 years will be the completion of a series of clinical trials that first demonstrate significant anti-tumor activity in man and ultimately demonstrate significantly prolonged survival of cancer patients bearing liquid or solid tumors that express antigens to be recognized by our modified innate immune products.